1159 PCSK9 inhibition interrupts the cross talk between keratinocytes and macrophages and prevents UVB-induced skin damage

The study was aim to examine the role and mechanism of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in ultraviolet B (UVB)-induced skin damage. PCSK9 is an enzyme that promotes the degradation of low-density lipoprotein receptors. It is involved in hyperlipidemia as well as other diseases, such as cancer and skin inflammation. However, the detail mechanism for PCSK9 on skin lesions was not clear. Thus, we aimed to examine the role and possible action mechanism of PCSK9 in UVB-induced skin damage. A small molecule inhibitor (SBC110736) against PCSK9 and siRNA duplexes targeting mouse PCSK9 were designed and applied. Their effects on various UVB-activated proteins were investigated. A co-culture system using UVB-treated keratinocytes supernatant was used to stimulate macrophages and observe its effect on the stimulator of interferon genes (STING) pathway activation. Immunohistochemical staining revealed a significant increase in PCSK9 expression after UVB exposure, indicating the possible role of PCSK9 in UVB damage. Skin damage, increase in epidermal thickness, and keratinocyte hyperproliferation was significantly alleviated after treatment with SBC110736 or siRNA duplexes, compared with that in the UVB model group. Notably, UVB exposure triggered DNA damage in keratinocytes, whereas substantial interferon regulatory factor 3 (IRF3) activation was observed in macrophages. In the co-culture system, supernatant from UVB-treated keratinocyte induced IRF3 activation in macrophages. This activation was inhibited with SBC110736 and by PCSK9 knockdown. Collectively, our findings reveal that PCSK9 plays a critical role in the crosstalk between damaged keratinocytes and STING activation in macrophages. The interruption of this crosstalk by PCSK9 inhibition may be a potential therapeutic strategy for UVB-induced skin damage.